Abstract

The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such "controversial" results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

The effect of various gene knockouts on the storage of mast cell (MC) granule compounds

The figure depicts the granule contents of MCs from wild-type mice of C57BL/6 genetic background. MC granules can contain several preformed compounds, including serglycin proteoglycan, chymases (mMCP-1, mMCP-2, mMCP-4, mMCP-5), tryptases (mMCP-6; mMCP-7 is absent in C57BL/6 mice), CPA3, bioactive amines (histamine, serotonin), various lysosomal hydrolases (such as β-hexosaminidase), and certain cytokines. For simplicity, a hypothetical granule of mixed “CTMC” (expressing mMCP-4, mMCP-5, mMCP-6, CPA3)/“MMC” (expressing mMCP-1, mMCP-2) phenotype is shown. As indicated, many of the granule compounds are stored in complex with serglycin proteoglycan and the absence of serglycin results in impaired storage of such compounds. However, note that several granule constituents (such as mMCP-1) are stored independently of serglycin, whereas others (such as mMCP-2) depend only partially on serglycin for storage. It is not yet established whether any cytokines which can be found in granules depend on serglycin for storage (indicated by “?” in the figure). Note that the absence of CPA3 leads to a secondary defect in the storage of mMCP-5 and vice versa; that is, the absence of mMCP-5 results in impaired CPA3 storage. In contrast, the absence of mMCP-4 or mMCP-6 does not induce pronounced effects on the storage of other granule mediators.

In the depicted model of allergic airway inflammation (see ; , ; ; , ), challenge of sensitized C57BL/6 and WBB6F1 mice with allergen via the airways i.n. produces different tissue responses in c-kit mutant mice lacking MCs or mMCPT-4 than in the corresponding wild-type mice. In mice lacking MCs (A), allergen challenge induces lower levels of AHR to methacholine challenge, airway inflammation, and tissue changes compared to those observed when MCs are present (B and C). (B) In the presence of wild-type MCs, the binding of allergen by IgE molecules bound to adjacent FcεRI molecules induces FcεRI aggregation, activating MCs to secrete preformed mediators (e.g., mMCP-4 and some TNF), lipid mediators, and many cytokines, chemokines, and growth factors. Some aeroallergens (e.g., HDM) can directly induce MC degranulation and secretion of mMCP-4. The secreted mediators can induce migration, maturation, and activation of DCs, amplify inflammatory responses and TH2 cytokine production, enhance AHR, and promote tissue changes, such as goblet cell metaplasia and overproduction of mucus, collagen deposition, and hyperplasia of airway smooth muscle cells. The activation of airway MCs can potentially be modulated by tissue factors, e.g., IFNγ, S1P, adenosine, and IL-33, or by cells, e.g., TH2 cells and Treg cells, which may be present in these sites. Studies in MC knockin mice indicate that some actions of MCs (such as increasing the numbers of epithelial goblet cells) can occur in a model of chronic asthma by MC-dependent mechanisms that do not require MC signaling via the FcεRIγ chain, whereas MCs must express both the FcεRIγ chain and the INFγR to mediate robust increases in lung eosinophils, neutrophils, and collagen (, ). (C) In Mcpt4−/− mice which have MCs but lack MC-associated mMCP-4, there are higher levels of serum IgE after sensitization, which may result in increased IgE levels in the airway tissues, as is depicted in the figure. The increased levels of IgE can favor the expression of increased numbers of FcεRI on MCs and basophils. Moreover, compared to the airway changes in wild-type mice (B), in mMCP-4-deficient mice (C), allergen challenge induces exacerbated AHR and enhanced thickening of airway smooth muscle, increased levels of inflammatory cell infiltration (with increases in eosinophils, lymphocytes, and neutrophils), and elevated levels of IL-33 in the airway. In wild-type mice (B), the degradation of IL-33 by MC-derived mMCP-4 can potentially dampen IL-33-mediated eosinophil recruitment, TH2 responses, and IgE production. AHR, airway hyper-responsiveness; TNF, tumor necrosis factor; HDM, house dust mite; DCs, dendritic cells; IFNγ, interferon γ; S1P, sphingosine-1-phosphate.